US5599794A - Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic - Google Patents
Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic Download PDFInfo
- Publication number
- US5599794A US5599794A US08/051,722 US5172293A US5599794A US 5599794 A US5599794 A US 5599794A US 5172293 A US5172293 A US 5172293A US 5599794 A US5599794 A US 5599794A
- Authority
- US
- United States
- Prior art keywords
- omeprazole
- acid
- antibiotic
- acid degradable
- substance
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods
- A61B17/04—Surgical instruments, devices or methods for suturing wounds; Holders or packages for needles or suture materials
- A61B17/0469—Suturing instruments for use in minimally invasive surgery, e.g. endoscopic surgery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods
- A61B17/04—Surgical instruments, devices or methods for suturing wounds; Holders or packages for needles or suture materials
- A61B17/06—Needles ; Sutures; Needle-suture combinations; Holders or packages for needles or suture materials
- A61B17/06066—Needles, e.g. needle tip configurations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods
- A61B17/34—Trocars; Puncturing needles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
- A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
- A61F2002/3006—Properties of materials and coating materials
- A61F2002/30092—Properties of materials and coating materials using shape memory or superelastic materials, e.g. nitinol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2210/0014—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof using shape memory or superelastic materials, e.g. nitinol
- A61F2210/0023—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof using shape memory or superelastic materials, e.g. nitinol operated at different temperatures whilst inside or touching the human body, heated or cooled by external energy source or cold supply
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2210/0014—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof using shape memory or superelastic materials, e.g. nitinol
- A61F2210/0023—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof using shape memory or superelastic materials, e.g. nitinol operated at different temperatures whilst inside or touching the human body, heated or cooled by external energy source or cold supply
- A61F2210/0047—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof using shape memory or superelastic materials, e.g. nitinol operated at different temperatures whilst inside or touching the human body, heated or cooled by external energy source or cold supply heated by light
Definitions
- the present invention relates to a combination of a substance with inhibiting effect on the gastric acid secretion, thus a substance which increases the intragastric pH e.g. proton pump inhibitors, histamin-H 2 -blockers and one or more antibacterial compounds which are acid degradable.
- a substance which increases the intragastric pH e.g. proton pump inhibitors, histamin-H 2 -blockers and one or more antibacterial compounds which are acid degradable.
- Helicobacter pylori is affected by certain antibiotic compounds e.g. macrolides and penicillins as has been shown in vitro and in vivo. However, these products are degraded into nonantibacterial metabolites in the presence of gastric acid, which drastically reduces their antibacterial efficacy.
- Proton inhibitors e.g. omeprazole and its pharmaceutically acceptable salts which are used in accordance with the invention, are known compounds, e.g. from EP 5129 and EP 124495 and can be produced by known processes. From US 5093342 it is also known that omeprazole can be used in the treatment of Helicobacter infections. Further it has earlier been proposed in WO 92/04898 to use a specific antibiotic, amoxycillin, which is stable in gastric acid, in combination with pantoprazole in the treatment of duodenal ulcers. No specific test data are included in said document.
- FIG. 1 represents a graph showing the blood serum levels of erythromycin Ery-Max® in healthy subjects during treatment with and without omeprazole;
- FIG. 2 represents a graph showing the blood serum levels of clarithromycin in healthy subjects during with treatment and without omeprazole.
- the new combination is especially directed to the treatment of gastropathies e.g. induced by Helicobacter pylori infections.
- Helicobacter pylori is a gram-negative spirilliform bacterium which colonises in the gastric mucosa. Treatment with commonly used acid degradable antibiotics alone has given insufficient effect.
- the salt of omeprazole according to the invention is an alkaline pharmaceutically acceptable salt.
- examples of such salts include inorganic salts, such as alkali metal salts, e.g. sodium salt, potassium salt etc., alkaline earth metal salts, e.g. calcium salt, magnesium salt etc., ammonium salt, organic salts such as organic amine salts, e.g.
- trimethylamine salt triethylamine salt, pyridine salt, procaine acid, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethytamino)methane salt, phenylethylbenzylamine salt, dibenzylethylenediamine salt.
- proton pump inhibitors such as lansoprazole may be used according to the invention.
- the antibiotic used in the combination should be of the kind, which has a bioavailability which may be improved due to elevation of intragastric pH. It should also be an antimicrobial compound with a very narrow spectrum e.g. benzylpenicillin.
- acid degradable and acid semi-stable macrolides e.g. erythromycin base and clarithromycin (Nakagawa et al., Chem. Pharm. Bull., 1992, 40, 725-28).
- antibiotics and/or salts thereof which are pharmaceutically enginered for acid protection like for instance enteric coating (e.g. Ery-Max®).
- the combination according to the present invention can be produced in one pharmaceutical formulation comprising both active ingredients or in two separate tablets or capsules, powder, mixture, effervescence tablets or solution.
- the active ingredients according to the invention are administered in the form of a pharmaceutical preparation containing the active ingredients as such (e.g. the free base in the case of erythromycin) or in the case of omeprazole also as a salt thereof in combination with a pharmaceutically acceptable carrier by the oral or parenteral route.
- the carrier mentioned above may be a solid, semi-solid or liquid diluent or a capsule.
- Compatible dosage forms include various types of tablets, capsules, granules, powders, oral liquids, injections and so on.
- the proportions of the active ingredient in the total composition is generally 0.1 to 100 weight percent and preferably 0.1 to 95 weight percent.
- the active ingredient can be formulated with a solid particulate carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, a cellulose derivative or gelatin, and a lubricating agent such as magnesium stearate, calcium stearate or polyethylene glycol wax may be further incorporated.
- a solid particulate carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, a cellulose derivative or gelatin
- a lubricating agent such as magnesium stearate, calcium stearate or polyethylene glycol wax may be further incorporated.
- the resulting composition is then compressed into tablets.
- Coated tablets or dragees can be manufactured by coating the core tablets, thus prepared, with a thick sugar solution containing gum arabic, gelatin, talc, titanium dioxide, etc. or a lacquer prepared using a volatile organic solvent or solvent mixture.
- Soft gelatin capsules can be manufactured by filling a composition comprising the active ingredient and a known vegetable oil into capsules.
- Hard gelatin capsules can be manufactured by filling into capsules the granules or pellets each comprising the active ingredient and a solid particulate carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, a cellulose derivative or gelatin.
- omeprazole or a salt thereof and the antibiotic depends on individual needs (for example, the patient's condition, body weight, age, sex, etc.) as well as on the method of administration.
- the oral dosage may range from 1 to 200 mg of omeprazole per day and up to 10 g of acid degradable antibiotic per adult human. Each may be administered in one to a few divided doses.
- the best mode of carrying out the invention at present is to combine omeprazole with erythromycin.
- the advantage of the present combination of a compound that increases the intragastric pH, such as omeprazole and an acid degradable antibiotic, is that the bioavailability of the antibiotic will increase resulting in sufficient plasma levels for therapeutic effects. Another advantage is that there will be increased amounts of the acid degradable antibiotic in the gastric lumen.
- Benzylpenicillin is interesting because it has a very narrow spectrum and therefore exerts a very limited effect on the normal intestinal flora.
- antibiotics which are weak bases e.g. macrolides will be excreted via the stomach wall due to its physico-chemical properties in congruence with other known weak bases i.e. nicotine, aminopurine and omeprazole (Larsson et al., Scand. J. Gastroenterol., 1983, 85, 900-7).
- the antibiotic weak base will be biologically concentrated in the stomach wall, where the bacteria (e.g. Helicobacter pylori) reside.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Medical Informatics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention consists of a combination of a substance that increases the intragastric pH and an acid degradable antibacterial compound. By this combined product regimen it will be possible to obtain maximal local antibacterial effect of acid degradable antibiotics as well as enhanced bioavailability of the active antibiotic, thus resulting in higher amounts of the active compound in the gastric mucosa due to secretion of weak bases. Both pharmacological effects contribute to drastically increased antimicrobial capacity of acid degradable antibiotics to be used against local infections in the gastrointestinal tract causing gastritis and/or peptic ulcer. The invention also selects to the use of said combination and a process for the preparation thereof.
Description
The present invention relates to a combination of a substance with inhibiting effect on the gastric acid secretion, thus a substance which increases the intragastric pH e.g. proton pump inhibitors, histamin-H2 -blockers and one or more antibacterial compounds which are acid degradable.
In the treatment of the peptic ulcer disease current therapy aims at reducing the gastric acid secretion, thus resulting in a recess of the injuries in the gastro-intestinal tract. Inhibitors of the gastric acid secretion, proton pump inhibitors in particular, induce a rapid relief of pain and other symptoms associated with the ulcer disease. However, relapses of the disease is a documented fact. Since gastric antisecretory therapy only leads to reduction of the major tissue irritating factor, gastric acid, the plausible cause of the disease, Helicobacter pylori, remains mainly unaffected. (Helicobacter pylori was earlier named Campylobacter pylori.)
Helicobacter pylori is affected by certain antibiotic compounds e.g. macrolides and penicillins as has been shown in vitro and in vivo. However, these products are degraded into nonantibacterial metabolites in the presence of gastric acid, which drastically reduces their antibacterial efficacy.
In view of the widespread use of antimicrobial pharmaceuticals in the treatment of infectious diseases or for other purposes and the consequent emergence of drug-resistant strains, increased incidence of microbial substitution due to disturbance of the normal bacterial flora, changes in profile of infectious diseases, etc., there has been a constant demand for the development of new antimicrobial agents or combinations thereof.
Proton inhibitors e.g. omeprazole and its pharmaceutically acceptable salts, which are used in accordance with the invention, are known compounds, e.g. from EP 5129 and EP 124495 and can be produced by known processes. From US 5093342 it is also known that omeprazole can be used in the treatment of Helicobacter infections. Further it has earlier been proposed in WO 92/04898 to use a specific antibiotic, amoxycillin, which is stable in gastric acid, in combination with pantoprazole in the treatment of duodenal ulcers. No specific test data are included in said document.
From e.g. Science, Mar. 22, 1946, p. 359-361 it is known that if acid degradable penicillins are administered orally they will be destroyed by the acid content in the stomach.
Further it is described in Eur. J. Clin. Microbiol. Infect. Dis, August 1988, p. 566-569 that some acid degradable antibiotics are active in vitro against Helicobacter pylori.
It has now unexpectedly been found that a combination of a substance with inhibiting effect on the gastric acid secretion, thus a substance which increases the intragastric pH e.g. proton pump inhibitors, histamin-H2 -blockers and one or more antibacterial compounds which is acid degradable give high plasma concentration of the antibiotic following oral administration.
By reducing the acidity in the stomach it is possible to markedly increase the bioavailability of acid-degradable antibiotics thus leaving more of a given dose of the compound available for local antibacterial effect as well as for absorption. Selection of narrow-spectrum antibiotics e.g. benzylpenicillin is favourable since such antibiotics have few side-effects. Due to known physico-chemical properties in general of weak bases like for instance omeprazole, the selection of weak bases e.g. erythromycin favours an increased accumulation of the antibiotic in the stomach wall and gastric crypts where the microbs e.g. Helicobacter pylori resides.
Thus, by combining the components of the present invention synergism of the antibacterial effect of antibiotic compounds is achieved resulting in an improved therapeutic efficacy.
FIG. 1 represents a graph showing the blood serum levels of erythromycin Ery-Max® in healthy subjects during treatment with and without omeprazole; and
FIG. 2 represents a graph showing the blood serum levels of clarithromycin in healthy subjects during with treatment and without omeprazole.
The new combination is especially directed to the treatment of gastropathies e.g. induced by Helicobacter pylori infections. Helicobacter pylori is a gram-negative spirilliform bacterium which colonises in the gastric mucosa. Treatment with commonly used acid degradable antibiotics alone has given insufficient effect.
The combination of 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazole (generic name: omeprazole) or pharmaceutically acceptable salts thereof and an acid degradable antibiotic give an especially high plasma concentration of the antibiotic following oral administration.
The salt of omeprazole according to the invention is an alkaline pharmaceutically acceptable salt. Examples of such salts include inorganic salts, such as alkali metal salts, e.g. sodium salt, potassium salt etc., alkaline earth metal salts, e.g. calcium salt, magnesium salt etc., ammonium salt, organic salts such as organic amine salts, e.g. trimethylamine salt, triethylamine salt, pyridine salt, procaine acid, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethytamino)methane salt, phenylethylbenzylamine salt, dibenzylethylenediamine salt.
Also other proton pump inhibitors, such as lansoprazole may be used according to the invention. The antibiotic used in the combination should be of the kind, which has a bioavailability which may be improved due to elevation of intragastric pH. It should also be an antimicrobial compound with a very narrow spectrum e.g. benzylpenicillin.
Other examples are acid degradable and acid semi-stable macrolides e.g. erythromycin base and clarithromycin (Nakagawa et al., Chem. Pharm. Bull., 1992, 40, 725-28). Further examples are antibiotics and/or salts thereof which are pharmaceutically enginered for acid protection like for instance enteric coating (e.g. Ery-Max®).
The antibacterial activity against Helicobacter pylori as indicated by MIC-values of macrolides is drastically decreased with increased pH of the medium in vitro (Melanoski et al., ICAAC, 1992, abstract 713, p 229).
The combination according to the present invention can be produced in one pharmaceutical formulation comprising both active ingredients or in two separate tablets or capsules, powder, mixture, effervescence tablets or solution.
The active ingredients according to the invention are administered in the form of a pharmaceutical preparation containing the active ingredients as such (e.g. the free base in the case of erythromycin) or in the case of omeprazole also as a salt thereof in combination with a pharmaceutically acceptable carrier by the oral or parenteral route. The carrier mentioned above may be a solid, semi-solid or liquid diluent or a capsule. Compatible dosage forms include various types of tablets, capsules, granules, powders, oral liquids, injections and so on. The proportions of the active ingredient in the total composition is generally 0.1 to 100 weight percent and preferably 0.1 to 95 weight percent.
In the manufacture of a pharmaceutical preparation for oral administration, the active ingredient can be formulated with a solid particulate carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, a cellulose derivative or gelatin, and a lubricating agent such as magnesium stearate, calcium stearate or polyethylene glycol wax may be further incorporated. The resulting composition is then compressed into tablets. Coated tablets or dragees can be manufactured by coating the core tablets, thus prepared, with a thick sugar solution containing gum arabic, gelatin, talc, titanium dioxide, etc. or a lacquer prepared using a volatile organic solvent or solvent mixture.
Soft gelatin capsules can be manufactured by filling a composition comprising the active ingredient and a known vegetable oil into capsules. Hard gelatin capsules can be manufactured by filling into capsules the granules or pellets each comprising the active ingredient and a solid particulate carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, a cellulose derivative or gelatin.
The dosage of omeprazole or a salt thereof and the antibiotic depends on individual needs (for example, the patient's condition, body weight, age, sex, etc.) as well as on the method of administration. Generally speaking, the oral dosage may range from 1 to 200 mg of omeprazole per day and up to 10 g of acid degradable antibiotic per adult human. Each may be administered in one to a few divided doses.
Benzylpenicillin was administered alone to eight healthy volunteers and in combination with omeprazole and the plasma concentration was measured. When benzylpenicillin was administered alone the plasma concentrations which were expressed in terms of the area under the plasma concentration-time curve, AUC (mg-h/L), and the maximum concentration, Cmax (mg/L), and time, T, or maximum time, Tmax (h or min), were insufficient for a therapeutical effect (Table 1). When benzylpenicillin was combined with omeprazole therapeutical useful plasma concentrations were reached (Table 2). Similar results were obtained after oral administration of erythromycin lactobionate prior and after omeprazole induced reduction of acid secretion in man (Tables 3 and 4). Semidegradable macrolides, e.g. Ery-Max® and clarithromycin are absorbed to a certain extent (Tables 5 and 7). However, after administration of an acid secretion inhibitor, omeprazole, a marked increase of the bioavailability of the macrolides is shown as indicated by the difference in Cmax and AUC in healthy volunteers (Tables 6 and 8). Compare also FIG. 1 and FIG. 2 showing the accurate plasma concentrations of Ery-Max® and clarithromycin with and without omeprazole. The high plasma concentrations of the antibiotics after reduction of the gastric acid secretion is evidence for a great reduction of the degradation in the stomach of the antibiotics used. This results in an increased amount of the active antibiotic in the gastric lumen, thus resulting in increased local antimicrobial effect. It also leads to a larger amount of the antibiotic available for absorption, thus resulting in increased plasma and tissue levels of the antibiotic (increased bioavailability). The best mode of carrying out the invention at present is to combine omeprazole with erythromycin.
TABLE 1
__________________________________________________________________________
Concentration in plasma of benzylpenicillin after oral administration
Dose 1.0 g. (without omeprazole)
Person
Plasma concentration mg/L Cmax
AUC
number
15'
30'
45'
1 h
1.5 h
2 h
3 h
4 h 6 h mg/L
H.mg/L
__________________________________________________________________________
1 0.24
0.50
0.54
0.41
0.22
0.135
0.074
<0.02
<0.02
0.54
0.81
2 0.53
1.60
1.47
1.24
0.52
0.30
0.14
0.063
<0.02
1.60
2.06
3 0.23
0.51
0.45
0.37
0.21
0.11
0.051
0.016
<0.02
0.51
0.69
4 0.076
0.23
0.20
0.15
0.084
0.053
0.044
0.023
<0.02
0.23
0.38
5 0.26
0.50
0.41
0.40
0.28
0.17
0.071
0.042
<0.02
0.50
0.84
6 0.33
0.37
0.26
0.20
0.099
0.051
0.038
<0.02
<0.02
0.37
0.48
7 0.17
0.26
0.23
0.17
0.14
0.075
0.027
<0.02
<0.02
0.26
0.39
8 0.104
0.125
0.124
0.121
0.062
0.050
0.021
<0.02
<0.02
0.125
0.24
Mean value
0.24
0.51
0.46
0.38
0.20
0.118
0.058
<0.03
<0.02
0.52
0.74
±S.D. 0.46
0.58
__________________________________________________________________________
Cmax: tdep = 4.163 P < 0.01
AUC: tdep = 5.553 P < 0.001
TABLE 2
__________________________________________________________________________
Concentration in plasma of benzylpenicillin after oral administration
Dose 1.0 g. (with omeprazole)
Person
Plasma concentration mg/L Cmax
AUC
number
15'
30'
45'
1 h
1.5 h
2 h
3 h
4 h
6 h
mg/L
H.mg/L
__________________________________________________________________________
1 0.89
2.98
3.25
3.41
3.74
2.79
0.89
0.70
0.25
3.74
9.54
2 0.73
2.80
5.51
5.74
2.26
1.62
0.84
0.76
0.28
5.74
9.52
3 1.40
6.24
9.85
9.75
6.59
1.67
0.53
0.30
0.061
9.85
13.20
4 0.11
0.72
1.22
3.05
7.57
5.59
2.94
0.45
0.094
7.57
12.80
5 0.64
2.48
2.45
2.10
1.95
1.10
0.46
0.25
0.054
2.48
4.82
6 1.24
3.22
3.65
3.57
1.42
0.84
0.55
0.33
0.074
3.65
5.78
7 0.33
0.83
1.43
1.52
1.17
0.87
0.45
0.21
0.074
1.52
3.34
8 0.62
1.37
2.31
2.35
2.54
1.37
0.48
0.23
0.041
2.54
5.00
Mean value
0.745
2.58
3.71
3.94
3.41
1.98
0.89
0.40
0.116
4.64
8.00
±S.D. 2.87
3.79
__________________________________________________________________________
Cmax: tdep = 4.163 P < 0.01
AUC: tdep = 5.553 P < 0.001
TABLE 3 1(2)
__________________________________________________________________________
Concentration in plasma of erythromycin lactobionate after oral
administration.
Dose 1.0 g. Without preceding omeprazole treatment
Subject
Serum levels in mg/L at indicated times
number
0 15' 30' 45' 1 h 1.5 h
2 h 3 h 4 h 6 h
__________________________________________________________________________
1 <0.015
0.015
0.15
0.29
0.28
0.20
0.18
0.13
0.091
0.047
2 <0.015
0.26
0.33
0.30
0.25
0.25
0.18
0.15
0.16
0.070
3 <0.015
0.042
0.22
0.21
0.24
0.14
0.13
0.12
0.86
0.049
4 <0.015
0.032
0.042
0.030
0.039
0.078
0.084
0.076
0.072
0.046
5 <0.015
0.023
0.13
0.16
0.16
0.15
0.14
0.12
0.082
0.051
6 <0.015
0.068
0.12
0.094
0.11
0.098
0.077
0.074
0.059
0.034
7 <0.015
0.57
0.98
0.75
0.68
0.43
0.37
0.32
0.27
0.088
8 <0.015
0.071
0.27
0.33
0.23
0.16
0.16
0.12
0.095
0.044
Mean value
<0.015
0.135
0.28
0.27
0.25
0.18
0.165
0.14
0.11
0.054
±S.D. ±0.193
±0.30
±0.22
±0.19
±0.11
±0.092
±0.078
±0.070
±0.017
__________________________________________________________________________
TABLE 3 2(2)
__________________________________________________________________________
Concentration in plasma of erythromycin lactobionate after oral
administration.
Dose 1.0 g. With preceding omeprazole treatment
Subject
Serum levels in mg/L at indicated times
number
0 15' 30' 45' 1 h 1.5 h
2 h 3 h 4 h 6 h
__________________________________________________________________________
1 <0.015
2.9 7.5 7.6 7.2 4.9 4.0 3.1 3.5 1.4
2 <0.015
2.3 6.8 5.7 4.5 5.3 3.6 3.3 3.2 1.4
3 <0.015
2.7 12.7
10.9
7.8 6.0 5.3 4.5 4.0 2.4
4 <0.015
3.2 6.0 3.3 2.5 1.9 2.8 2.4 2.4 0.82
5 <0.015
0.25
2.8 6.4 4.8 3.0 2.5 2.0 2.8 1.2
6 <0.015
1.5 4.9 3.4 2.7 1.6 1.8 1.6 2.1 0.89
7 <0.015
6.3 9.8 9.3 6.2 5.3 4.6 4.6 3.9 1.8
8 <0.015
3.8 12.8
13.0
11.1
10.7 7.3 5.6 4.3 2.2
Mean value
<0.015
2.87
7.91
7.45
5.85
4.84 3.99
3.39
3.28
1.51
±S.D. ±1.77
±3.60
±3.46
±2.86
±2.89
±1.76
±1.40
±0.79
±0.58
__________________________________________________________________________
TABLE 4
______________________________________
Kinetic data following oral administration(s) of
erythromycin lactobionate to 8 healthy volunteers with and
without co-administration of omeprazole. A cross over study.
C.sub.max T.sub.max
AUC
mg/L h H.mg/L
Omeprazole mean ± SD median 0-6 H
______________________________________
YES 8.38 ± 0.28
0.5 21.74 ± 8.64
NO 0.32 ± 0.28
0.75 0.83 ± 0.55
______________________________________
TABLE 5 1(2)
__________________________________________________________________________
Blood serum levels of erythromycin Ery-Max ® following oral
administration.
Dose 500 mg. Without omeprazole treatment.
Subject
Serum levels in mg/L at indicated times (min)
number
0 30 60 90 120
150
180
300
480
720
__________________________________________________________________________
1 0.00
0.06
0.06
0.06
0.12
0.28
1.90
0.76
0.15
0.06
2 0.00
0.06
0.06
0.06
0.06
0.06
0.06
0.65
0.19
0.06
3 0.00
0.06
0.06
0.06
0.06
0.08
0.75
0.49
0.20
0.06
4 0.00
0.06
0.06
0.06
0.06
0.16
0.43
0.92
0.25
0.07
5 0.00
0.06
0.06
0.06
0.06
0.25
0.95
1.50
0.45
0.07
6 0.00
0.06
0.06
0.06
0.06
0.06
0.06
0.52
0.17
0.06
7 0.00
0.06
0.10
0.38
0.41
0.68
1.10
0.46
0.20
0.06
8 0.00
0.06
0.06
0.06
0.51
1.20
1.70
0.86
0.31
0.06
Mean 0.00
0.06
0.07
0.10
0.17
0.35
0.87
0.77
0.24
0.06
Sdev 0.00
0.00
0.01
0.11
0.18
0.40
0.69
0.34
0.10
0.01
__________________________________________________________________________
TABLE 5 2(2)
__________________________________________________________________________
Blood serum levels of erythromycin Ery-Max ® following oral
administration.
Dose 500 mg. Without preceding omeprazole treatment
Subject
AUC levels at indicated times (min)
number
0 30 60 90 120
150
180
300
480
720
Tot AUC
__________________________________________________________________________
1 0 0.015
0.03
0.03
0.045
0.1
0.545
2.66
1.365
0.42
5.21
2 0 0.015
0.03
0.03
0.03
0.03
0.03
0.71
1.26
0.5
2.635
3 0 0.015
0.03
0.03
0.03
0.036
0.208
1.24
1.035
0.52
3.144
4 0 0.015
0.03
0.03
0.03
0.055
0.148
1.35
1.755
0.646
4.059
5 0 0.015
0.03
0.03
0.03
0.078
0.3
2.45
2.925
1.036
6.894
6 0 0.015
0.03
0.03
0.03
0.03
0.03
0.58
1.035
0.46
2.24
7 0 0.015
0.04
0.12
0.198
0.273
0.445
1.56
0.99
0.52
4.16
8 0 0.015
0.03
0.03
0.143
0.428
0.725
2.56
1.755
0.74
6.425
Mean 0 0.015
0.031
0.041
0.067
0.129
0.304
1.639
1.515
0.605
Sdev 0 0.015
0.004
0.032
0.066
0.145
0.25
0.827
0.647
0.202
__________________________________________________________________________
AUC: 4.34 ± 1.7
C.sub.max : 1.005
TABLE 6 1(2)
__________________________________________________________________________
Blood serum levels of erythromycin Ery-Max ® following oral
administration.
Dose 250 mg. With preceding omeprazole treatment.
Subject
Serum levels in mg/L at indicated times (min)
number
0 30 60 90 120
150
180
300
480
720
__________________________________________________________________________
1 0.00
0.06
0.54
3.2
2.4
2.3
1.9
0.79
0.22
0.06
2 0.00
0.06
0.06
0.1
0.69
2.1
1.7
0.54
0.14
0.06
3 0.00
0.06
0.29
1.2
2.5
2.5
1.4
0.75
0.23
0.06
4 0.00
0.06
0.06
0.094
0.84
0.74
0.37
1.3
0.45
0.081
5 0.00
0.06
0.06
0.059
0.58
1.5
1.7
1.6
0.5
0.084
6 0.00
0.06
0.068
0.49
1.2
0.86
0.68
0.48
0.14
0.06
7 0.00
0.06
0.057
1.1
1.3
2 2.1
0.87
0.27
0.087
8 0.00
0.06
0.48
1.4
1.9
1.6
1.7
1 0.28
0.084
Mean 0.00
0.06
0.20
0.96
1.43
1.7
1.44
0.92
0.28
0.07
Sdev 0.00
0.00
0.21
1.06
0.76
0.65
0.61
0.38
0.13
0.01
__________________________________________________________________________
TABLE 6 2(2)
__________________________________________________________________________
Blood serum levels of erythromycin Ery-Max ® following oral
administration.
Dose 250 mg. With preceding omeprazole treatment.
Subject
AUC levels at indicated times (min)
number
0 30 60 90 120
150
180
300
480
720
Tot AUC
__________________________________________________________________________
1 0.00
0.015
0.15
0.935
1.4
1.175
1.05
2.69
1.515
0.56
9.49
2 0.00
0.015
0.03
0.04
0.198
0.698
0.95
2.24
1.02
0.4
5.59
3 0.00
0.015
0.088
0.373
0.925
1.25
0.975
2.15
1.47
0.58
7.825
4 0.00
0.015
0.03
0.039
0.234
0.395
0.278
1.67
2.625
1.062
6.347
5 0.00
0.015
0.03
0.03
0.16
0.52
0.8
3.3
3.15
1.168
9.173
6 0.00
0.015
0.032
0.14
0.423
0.515
0.385
1.16
0.93
0.4
3.999
7 0.00
0.015
0.029
0.289
0.6
0.825
1.025
2.97
1.71
0.714
8.187
8 0.00
0.015
0.0135
0.47
0.825
0.875
0.825
2.7
1.92
0.728
8.493
Mean 0.00
0.015
0.065
0.289
0.595
0.782
0.786
2.36
1.793
0.702
Sdev 0.00
0.00
0.052
0.31
0.434
0.312
0.295
0.703
0.764
0.284
__________________________________________________________________________
AUC: 7.38 ± 1.9
C.sub.max : 1.94
TABLE 7 1(2)
__________________________________________________________________________
Blood serum levels of clarithromycin following oral administration.
Dose 250 mg. Without preceding omeprazole treatment
Subject
Serum levels in mg/L at indicated times (min)
number
0 30 60 90 120
150
180
360
660
840
__________________________________________________________________________
1 0.00
0.11
0.97
0.92
1.1
1.5
1.2
0.96
0.41
0.26
2 0.00
0.12
0.15
0.24
0.28
0.36
0.47
0.53
0.18
0.14
3 0.00
0.06
0.11
0.092
0.11
0.12
0.17
0.55
0.2
0.12
4 0.00
0.06
0.06
0.044
0.099
0.13
0.15
0.48
0.23
0.13
5 0.00
0.06
0.06
0.062
0.064
0.13
0.18
0.54
0.2
0.16
6 0.00
0.07
0.13
0.2
0.3
0.37
0.45
0.23
0.14
0.082
7 0.00
0.12
0.26
0.27
0.46
0.81
0.78
0.64
0.2
0.12
8 0.00
0.06
0.31
0.38
0.41
0.55
0.57
0.64
0.27
0.16
Mean 0.00
0.08
0.26
0.28
0.35
0.50
0.50
0.57
0.23
0.15
Sdev 0.00
0.03
0.30
0.28
0.34
0.47
0.36
0.20
0.08
0.05
__________________________________________________________________________
TABLE 7 2(2)
__________________________________________________________________________
Blood serum levels of clarithromycin following oral administration.
Dose 250 mg. Without preceding omeprazole treatment
Subject
AUC levels at indicated times (min)
number
0 30 60 90 120
150
180
360
660
840
Tot AUC
__________________________________________________________________________
1 0.00
0.028
0.27
0.473
0.505
0.65
0.675
2.16
4.11
1.005
9.875
2 0.00
0.03
0.068
0.098
0.13
0.16
0.208
1 2.13
0.48
4.303
3 0.00
0.015
0.043
0.051
0.051
0.058
0.073
0.72
2.25
0.48
3.739
4 0.00
0.015
0.03
0.026
0.036
0.057
0.07
0.63
2.13
0.54
3.534
5 0.00
0.015
0.03
0.031
0.032
0.049
0.078
0.72
2.22
0.54
3.713
6 0.00
0.018
0.05
0.083
0.125
0.168
0.205
0.68
1.11
0.333
2.771
7 0.00
0.03
0.095
0.133
0.183
0.318
0.398
1.42
2.52
0.48
5.575
8 0.00
0.015
0.093
0.173
0.198
0.24
0.28
1.21
2.73
0.645
5.583
Mean 0.00
0.021
0.085
0.133
0.157
0.212
0.248
1.068
2.4
0.563
Sdev 0.00
0.007
0.079
0.146
0.154
0.201
0.207
0.525
0.838
0.199
__________________________________________________________________________
AUC: 4.88 ± 2.24
C.sub.max : 0.68
TABLE 8 1(2)
__________________________________________________________________________
Blood serum levels of clarithromycin following oral administration.
Dose 250 mg. With preceding omeprazole treatment.
Subject
Serum levels in mg/L at indicated times (min)
number
0 30 60 90 120
150
180
360
660
840
__________________________________________________________________________
1 0.00
1.9
2.3
2.2
1.7
1.7
1.7
0.86
0.37
0.28
2 0.00
0.078
3 1.9
1.9
1.9
1.7
0.78
0.34
0.16
3 0.00
0.6
1.6
1.3
1.1
1.1
1.05
0.68
0.23
0.14
4 0.00
0.06
1.2
1.3
1.2
1.03
1.1
0.68
0.39
0.2
5 0.00
0.096
2.1
1.6
1.3
1.1
1.1
0.77
0.27
0.18
6 0.00
0.21
1.2
1.8
1.6
1 1.5
0.67
0.22
0.13
7 0.00
0.12
0.99
1.1
0.9
0.89
1.07
0.61
0.22
0.16
8 0.00
1.07
2.2
2 2 1.7
1.8
0.92
0.38
0.24
Mean 0.00
0.52
1.82
1.65
1.46
1.30
1.38
0.75
0.30
0.19
Sdev 0.00
0.66
0.69
0.39
0.40
0.39
0.33
0.11
0.08
0.05
__________________________________________________________________________
TABLE 8 2(2)
__________________________________________________________________________
Blood serum levels of clarithromycin following oral administration.
Dose 250 mg. With preceding omeprazole treatment.
Subject
AUC levels at indicated times (min)
number
0 30 60 90 120
150
180
360
660
840
Tot AUC
__________________________________________________________________________
1 0.00
0.475
1.05
1.125
0.975
0.85
0.85
2.56
3.69
0.975
12.55
2 0.00
0.02
0.77
1.225
0.95
0.95
0.9
2.48
3.36
0.75
11.4
3 0.00
0.15
0.55
0.725
0.6
0.55
0.538
1.73
2.73
0.555
8.128
4 0.00
0.015
0.315
0.625
0.625
0.558
0.533
1.78
3.21
0.885
8.545
5 0.00
0.024
0.549
0.925
0.725
0.6
0.55
1.87
3.12
0.675
9.038
6 0.00
0.053
0.353
0.75
0.85
0.65
0.625
2.17
2.67
0.525
8.645
7 0.00
0.03
0.278
0.523
0.5
0.448
0.49
1.68
2.49
0.57
7.008
8 0.00
0.268
0.818
1.05
1 0.925
0.875
2.72
3.9
0.93
12.49
Mean 0.00
0.129
0.585
0.868
0.778
0.691
0.67
2.124
3.146
0.733
Sdev 0.00
0.165
0.275
0.251
0.192
0.191
0.174
0.416
0.499
0.18
__________________________________________________________________________
AUC: 9.7 ± 2.1
C.sub.max : 1.9
The advantage of the present combination of a compound that increases the intragastric pH, such as omeprazole and an acid degradable antibiotic, is that the bioavailability of the antibiotic will increase resulting in sufficient plasma levels for therapeutic effects. Another advantage is that there will be increased amounts of the acid degradable antibiotic in the gastric lumen.
Benzylpenicillin is interesting because it has a very narrow spectrum and therefore exerts a very limited effect on the normal intestinal flora.
By reducing the gastric acid secretion or acid neutralisation in the stomach the pH increases. Due to the less acidic miliew the orally administered acid degradable antibiotic will be less catabolized and thus locally exerting its antimicrobial effect. Another advantage is that increased amounts of the antibiotic will pass into the small intestine where it will be absorbed in biologically active form. Increasing the intragastric pH is also favourable for antibiotic efficacy as shown in vitro. If the pH of the medium where Helicobacter pylori is grown in vitro is reduced varying degrees below pH 7 the antibacterial properties rapidly decrease.
Those antibiotics which are weak bases e.g. macrolides will be excreted via the stomach wall due to its physico-chemical properties in congruence with other known weak bases i.e. nicotine, aminopurine and omeprazole (Larsson et al., Scand. J. Gastroenterol., 1983, 85, 900-7). Thus, the antibiotic weak base will be biologically concentrated in the stomach wall, where the bacteria (e.g. Helicobacter pylori) reside.
Claims (2)
1. A synergistic combination comprising from about 1-200 mg omeprazole or a pharmaceutically acceptable salt thereof and from about 250 mg to 10 mg clarithromycin for the treatment of gastritis and peptic ulcer.
2. A method of orally administering an acid degradable antibiotic so as to increase its bioavailability comprising an effective amount of the synergistic combination of claim 1 to a human.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/442,382 US5633244A (en) | 1992-04-24 | 1995-05-16 | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic |
| US08/441,766 US5629305A (en) | 1992-04-24 | 1995-05-16 | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9201297A SE9201297D0 (en) | 1992-04-24 | 1992-04-24 | SYNERGISTIC COMBINATION |
| SE9201297 | 1992-04-24 | ||
| SE9300029A SE9300029D0 (en) | 1993-01-08 | 1993-01-08 | SYNERGISTIC COMBINATION II |
| SE9300029 | 1993-01-08 |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/442,382 Division US5633244A (en) | 1992-04-24 | 1995-05-16 | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic |
| US08/441,766 Division US5629305A (en) | 1992-04-24 | 1995-05-16 | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US5599794A true US5599794A (en) | 1997-02-04 |
Family
ID=26661401
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/051,722 Expired - Fee Related US5599794A (en) | 1992-04-24 | 1993-04-22 | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic |
| US08/441,766 Expired - Lifetime US5629305A (en) | 1992-04-24 | 1995-05-16 | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic |
| US08/442,382 Expired - Lifetime US5633244A (en) | 1992-04-24 | 1995-05-16 | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/441,766 Expired - Lifetime US5629305A (en) | 1992-04-24 | 1995-05-16 | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic |
| US08/442,382 Expired - Lifetime US5633244A (en) | 1992-04-24 | 1995-05-16 | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic |
Country Status (38)
| Country | Link |
|---|---|
| US (3) | US5599794A (en) |
| EP (2) | EP0637241B1 (en) |
| JP (1) | JPH07505901A (en) |
| KR (1) | KR100340165B1 (en) |
| CN (1) | CN1041798C (en) |
| AP (1) | AP466A (en) |
| AT (1) | ATE194286T1 (en) |
| AU (1) | AU669903B2 (en) |
| CA (1) | CA2133762C (en) |
| CZ (1) | CZ291201B6 (en) |
| DE (2) | DE637241T1 (en) |
| DK (1) | DK0637241T3 (en) |
| DZ (1) | DZ1683A1 (en) |
| EE (1) | EE03149B1 (en) |
| ES (1) | ES2100135T3 (en) |
| FI (1) | FI944953A7 (en) |
| GR (2) | GR970300011T1 (en) |
| HR (1) | HRP930755B1 (en) |
| HU (1) | HUT71225A (en) |
| IL (1) | IL105155A (en) |
| IS (1) | IS3990A (en) |
| LV (1) | LV12625B (en) |
| MA (1) | MA22878A1 (en) |
| MY (1) | MY121189A (en) |
| NO (1) | NO314288B1 (en) |
| NZ (1) | NZ252759A (en) |
| PL (1) | PL173485B1 (en) |
| PT (1) | PT637241E (en) |
| RO (1) | RO115780B1 (en) |
| RU (1) | RU2143899C1 (en) |
| SG (1) | SG52485A1 (en) |
| SI (1) | SI9300219B (en) |
| SK (1) | SK282420B6 (en) |
| TN (1) | TNSN93040A1 (en) |
| TW (1) | TW276996B (en) |
| UA (1) | UA43830C2 (en) |
| WO (1) | WO1993021920A1 (en) |
| YU (1) | YU49091B (en) |
Cited By (39)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6077541A (en) * | 1997-11-14 | 2000-06-20 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| WO2000050037A1 (en) * | 1999-02-26 | 2000-08-31 | Nitromed, Inc. | Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use |
| US6117868A (en) * | 1998-09-16 | 2000-09-12 | Ed. Geistlich Sohne Ag Fur Chemische Industrie | Treatment of gastrointestinal ulcers or gastritis caused by microbial infection |
| US6132768A (en) * | 1995-07-05 | 2000-10-17 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors |
| US6136344A (en) * | 1995-02-06 | 2000-10-24 | Astra Aktiebolag | Oral pharmaceutical dosage form |
| US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6245913B1 (en) | 1999-06-30 | 2001-06-12 | Wockhardt Europe Limited | Synthetic procedure for 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-IH-benzimidazole hydrochloride and its conversion to omeprazole |
| US6262085B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6262086B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
| US6312723B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
| US6316020B1 (en) | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
| US6326384B1 (en) | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
| US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US20030099715A1 (en) * | 2000-03-28 | 2003-05-29 | Schwarz Franz Xaver | Granulated particles with masked taste |
| US6576258B1 (en) | 1997-07-14 | 2003-06-10 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. | Pharmaceutical formulation with controlled release of active substances |
| US20030119824A1 (en) * | 2000-01-05 | 2003-06-26 | Redmond H. Paul | Treatment of inflammatory bowel disease |
| US6645988B2 (en) | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US20040006111A1 (en) * | 2002-01-25 | 2004-01-08 | Kenneth Widder | Transmucosal delivery of proton pump inhibitors |
| US20040024014A1 (en) * | 2002-08-01 | 2004-02-05 | Nitromed, Inc. | Nitrosated proton pump inhibitors, compositions and methods of use |
| US6699885B2 (en) | 1996-01-04 | 2004-03-02 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and methods of using same |
| US6733778B1 (en) | 1999-08-27 | 2004-05-11 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6780880B1 (en) | 1999-08-26 | 2004-08-24 | Robert R. Whittle | FT-Raman spectroscopic measurement |
| US20040185092A1 (en) * | 2003-03-18 | 2004-09-23 | Yih Ming Hsiao | Pharmaceutical preparations of omeprazole and/or clarithromycin for oral use |
| US20040248942A1 (en) * | 2003-02-20 | 2004-12-09 | Bonnie Hepburn | Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid |
| US20040266828A1 (en) * | 1999-02-26 | 2004-12-30 | Nitromed, Inc. | Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use |
| US20050031700A1 (en) * | 2003-07-18 | 2005-02-10 | Sanatarus, Inc. | Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders |
| US20050037070A1 (en) * | 2003-07-18 | 2005-02-17 | Santarus, Inc. | Pharmaceutical formulatins useful for inhibiting acid secretion and methods for making and using them |
| US20050266071A1 (en) * | 2004-05-25 | 2005-12-01 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US20060147522A1 (en) * | 2004-05-25 | 2006-07-06 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US20060204585A1 (en) * | 2003-07-18 | 2006-09-14 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| WO2008067037A2 (en) | 2006-10-05 | 2008-06-05 | Santarus, Inc. | Novel formulations of proton pump inhibitors and methods of using these formulations |
| US20090092658A1 (en) * | 2007-10-05 | 2009-04-09 | Santarus, Inc. | Novel formulations of proton pump inhibitors and methods of using these formulations |
| EP2486910A2 (en) | 2006-10-27 | 2012-08-15 | The Curators Of The University Of Missouri | Multi-chambered apparatus comprising a dispenser head |
| USRE45198E1 (en) | 1996-01-04 | 2014-10-14 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
| WO2024075017A1 (en) | 2022-10-04 | 2024-04-11 | Zabirnyk Arsenii | Inhibition of aortic valve calcification |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW420610B (en) * | 1994-04-07 | 2001-02-01 | Pfizer | A pharmaceutical composition for treating a H. pylori infection or gastric or duodenal ulcers |
| CN1061232C (en) * | 1996-04-12 | 2001-01-31 | 马理国 | A Chinese medicinal composition for treating gastritis and ulcer |
| US6303644B1 (en) * | 1997-07-25 | 2001-10-16 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Proton pump inhibitor in therapeutic combination with antibacterial substances |
| US7365047B1 (en) | 1999-09-28 | 2008-04-29 | The Regents Of The University Of California | Use of pentagastrin to inhibit gastric acid secretion or as a diuretic |
| US6787342B2 (en) | 2000-02-16 | 2004-09-07 | Merial Limited | Paste formulations |
| IL151496A0 (en) * | 2000-02-29 | 2003-04-10 | Teva Pharma | Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same |
| CA2413923A1 (en) * | 2000-03-09 | 2001-09-13 | Andrew Ilchyshyn | Treatment of inflammatory dermatoses comprising erythromycin or clarythromycin metronidazole and a gastrointestinal hydrogen pump inhibitor |
| EP1133987A1 (en) * | 2000-03-09 | 2001-09-19 | Ian Whitcroft | Treatment of inflammatory dermatoses with combinations of erythromycin or clarythromycin, metronidazole and a hydrogen pump inhibitor |
| SE0002476D0 (en) | 2000-06-30 | 2000-06-30 | Astrazeneca Ab | New compounds |
| US6544556B1 (en) | 2000-09-11 | 2003-04-08 | Andrx Corporation | Pharmaceutical formulations containing a non-steroidal antiinflammatory drug and a proton pump inhibitor |
| US20020064555A1 (en) * | 2000-09-29 | 2002-05-30 | Dan Cullen | Proton pump inhibitor formulation |
| SE0103695D0 (en) | 2001-11-07 | 2001-11-07 | Thomas Boren | A novel non-antibiotic strategy against OGIP infections based on a cereal product |
| WO2003063927A2 (en) * | 2001-11-16 | 2003-08-07 | Eisai Co. Ltd | Compositions and methods to treat gastrointestinal disorders |
| US20030228363A1 (en) * | 2002-06-07 | 2003-12-11 | Patel Mahendra R. | Stabilized pharmaceutical compositons containing benzimidazole compounds |
| WO2004072061A1 (en) * | 2003-02-05 | 2004-08-26 | Teva Pharmaceutical Industries Ltd. | Method of stabilizing lansoprazole |
| US20060194748A1 (en) * | 2005-02-28 | 2006-08-31 | National University Corporation Nagoya University | Methods for treating disorders induced by H. pylori infections and pharmaceutical compositions for the same |
| WO2007070164A1 (en) * | 2005-10-19 | 2007-06-21 | The Curators Of The University Of Missouri | Pharmaceutical composition comprising a proton pump inhibitor, a buffering agent and an anti-h. pylori active substance and methods of using same |
| US20070141151A1 (en) * | 2005-12-20 | 2007-06-21 | Silver David I | Lansoprazole orally disintegrating tablets |
| US10869690B2 (en) * | 2017-06-29 | 2020-12-22 | Ethicon Llc | Trocar obturator with transverse needle ports |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990009175A1 (en) * | 1989-02-09 | 1990-08-23 | Aktiebolaget Hässle | Use of omeprazole as an antimicrobial agent |
| US5013743A (en) * | 1989-02-10 | 1991-05-07 | Takeda Chemical Industries, Ltd. | Selective antibacterial agent against campytobacter |
| WO1992004898A1 (en) * | 1990-09-14 | 1992-04-02 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Use of pyridylmethylsulphinyl-1h-benzimidazole derivates in the treatment of illnesses caused by helicobacter bacteria |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL85472A (en) * | 1987-03-09 | 1991-06-30 | Procter & Gamble | Pharmaceutical compositions for treating gastrointestinal disorders |
| GB9018603D0 (en) * | 1990-08-24 | 1990-10-10 | Smith Kline French Lab | Compositions |
-
1993
- 1993-03-24 IS IS3990A patent/IS3990A/en unknown
- 1993-03-24 TW TW082102192A patent/TW276996B/zh active
- 1993-03-24 IL IL10515593A patent/IL105155A/en active IP Right Review Request
- 1993-04-02 HR HR930755A patent/HRP930755B1/en not_active IP Right Cessation
- 1993-04-07 DZ DZ930044A patent/DZ1683A1/en active
- 1993-04-15 AP APAP/P/1993/000518A patent/AP466A/en active
- 1993-04-20 DK DK93912028T patent/DK0637241T3/en active
- 1993-04-20 NZ NZ252759A patent/NZ252759A/en not_active IP Right Cessation
- 1993-04-20 CA CA002133762A patent/CA2133762C/en not_active Expired - Lifetime
- 1993-04-20 WO PCT/SE1993/000327 patent/WO1993021920A1/en not_active Application Discontinuation
- 1993-04-20 AU AU42737/93A patent/AU669903B2/en not_active Ceased
- 1993-04-20 ES ES93912028T patent/ES2100135T3/en not_active Expired - Lifetime
- 1993-04-20 PL PL93305799A patent/PL173485B1/en unknown
- 1993-04-20 SK SK1275-94A patent/SK282420B6/en not_active IP Right Cessation
- 1993-04-20 HU HU9403069A patent/HUT71225A/en not_active Application Discontinuation
- 1993-04-20 PT PT93912028T patent/PT637241E/en unknown
- 1993-04-20 RU RU94045926A patent/RU2143899C1/en not_active IP Right Cessation
- 1993-04-20 DE DE0637241T patent/DE637241T1/en active Pending
- 1993-04-20 FI FI944953A patent/FI944953A7/en not_active Application Discontinuation
- 1993-04-20 UA UA94105962A patent/UA43830C2/en unknown
- 1993-04-20 DE DE69328967T patent/DE69328967T2/en not_active Revoked
- 1993-04-20 AT AT93912028T patent/ATE194286T1/en not_active IP Right Cessation
- 1993-04-20 CZ CZ19942593A patent/CZ291201B6/en not_active IP Right Cessation
- 1993-04-20 JP JP5519164A patent/JPH07505901A/en active Pending
- 1993-04-20 EP EP93912028A patent/EP0637241B1/en not_active Revoked
- 1993-04-20 RO RO94-01707A patent/RO115780B1/en unknown
- 1993-04-20 EP EP99108949A patent/EP0956857A3/en not_active Withdrawn
- 1993-04-20 SG SG1996005136A patent/SG52485A1/en unknown
- 1993-04-21 MA MA23171A patent/MA22878A1/en unknown
- 1993-04-21 YU YU27593A patent/YU49091B/en unknown
- 1993-04-22 US US08/051,722 patent/US5599794A/en not_active Expired - Fee Related
- 1993-04-23 MY MYPI93000749A patent/MY121189A/en unknown
- 1993-04-23 SI SI9300219A patent/SI9300219B/en not_active IP Right Cessation
- 1993-04-23 TN TNTNSN93040A patent/TNSN93040A1/en unknown
- 1993-04-24 CN CN93105000A patent/CN1041798C/en not_active Expired - Fee Related
-
1994
- 1994-10-21 NO NO19944010A patent/NO314288B1/en unknown
- 1994-10-22 KR KR1019940703767A patent/KR100340165B1/en not_active Expired - Fee Related
- 1994-11-17 EE EE9400418A patent/EE03149B1/en not_active IP Right Cessation
-
1995
- 1995-05-16 US US08/441,766 patent/US5629305A/en not_active Expired - Lifetime
- 1995-05-16 US US08/442,382 patent/US5633244A/en not_active Expired - Lifetime
-
1997
- 1997-05-30 GR GR970300011T patent/GR970300011T1/en unknown
-
2000
- 2000-09-21 GR GR20000402159T patent/GR3034470T3/en not_active IP Right Cessation
- 2000-10-16 LV LVP-00-139A patent/LV12625B/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990009175A1 (en) * | 1989-02-09 | 1990-08-23 | Aktiebolaget Hässle | Use of omeprazole as an antimicrobial agent |
| US5093342A (en) * | 1989-02-09 | 1992-03-03 | Aktiebolaget Hassle | Use of omeprazole as an antimicrobial agent |
| US5013743A (en) * | 1989-02-10 | 1991-05-07 | Takeda Chemical Industries, Ltd. | Selective antibacterial agent against campytobacter |
| WO1992004898A1 (en) * | 1990-09-14 | 1992-04-02 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Use of pyridylmethylsulphinyl-1h-benzimidazole derivates in the treatment of illnesses caused by helicobacter bacteria |
Non-Patent Citations (21)
| Title |
|---|
| "Which regimen for H pylori eradication?" SCRIP No. 1861 Oct. 5, 1983, p. 23. |
| Chemical Abstracts 104:203737 j (1986). * |
| Chemical Abstracts 106:182648l (1987). * |
| Goodwin, Worsley, Peptic Ulcer Disease, 1992, Current Science, 8:122 127. * |
| Goodwin, Worsley, Peptic Ulcer Disease, 1992, Current Science, 8:122-127. |
| Logan et al, The Lancet, vol. 340, Jul. 25, 1992 Abstract Drug Thev Boll 1991, 29; 26 reference (see foot note #9). |
| Logan et al, The Lancet, vol. 340, Jul. 25, 1992 Abstract Drug Thev Boll 1991, 29; 26 reference (see foot note 9). * |
| Loo, Sherman, Matlow; Helicobacter pylori Infection, Anti microbial Agents & Chemotherapy, May, 1992, pp. 1133 1135. * |
| Loo, Sherman, Matlow; Helicobacter pylori Infection, Anti-microbial Agents & Chemotherapy, May, 1992, pp. 1133-1135. |
| McDermott, et al., Science, The Absorption of Orally Administered Penicillin, Mar. 22, 1946, pp. 359 361. * |
| McDermott, et al., Science, The Absorption of Orally Administered Penicillin, Mar. 22, 1946, pp. 359-361. |
| McNulty, et al., Eur. J. Clin. Microbiol. Infect. Dis., Susceptibility of Clinical Isolates, Aug., 1988, pp. 566 569. * |
| McNulty, et al., Eur. J. Clin. Microbiol. Infect. Dis., Susceptibility of Clinical Isolates, Aug., 1988, pp. 566-569. |
| P. Unge, et al. "Does Omeprazole improve antimicrobial therapy directed towards gastric Campylobacter-pylori in patients with antral gastritis" Scandinavian Journal of Gastroenterology 1989, 24 (Suppl. 167) p. 49-54 (ARTICLE). |
| P. Unge, et al. "Does Omeprazole, 40 mg o.m. improve antimicrobial therapy directed towards gastric Campylobacter-pylori in patients . . . " Scandinavian Journal of Gastroenterology 1989, 24 (Suppl. 166) p. 184 (ABSTRACT). |
| P. Unge, et al. Does Omeprazole improve antimicrobial therapy directed towards gastric Campylobacter pylori in patients with antral gastritis Scandinavian Journal of Gastroenterology 1989, 24 (Suppl. 167) p. 49 54 (ARTICLE). * |
| P. Unge, et al. Does Omeprazole, 40 mg o.m. improve antimicrobial therapy directed towards gastric Campylobacter pylori in patients . . . Scandinavian Journal of Gastroenterology 1989, 24 (Suppl. 166) p. 184 (ABSTRACT). * |
| S. Rune, "Helicobacter pylori, Peptic Ulcer Disease and Inhibition of Gastric Acid Secretion" Digestion 1992; 51 (Suppl. 1): 11-16. |
| S. Rune, Helicobacter pylori, Peptic Ulcer Disease and Inhibition of Gastric Acid Secretion Digestion 1992; 51 (Suppl. 1): 11 16. * |
| The Lancet, Clarithromycin and Omeprazole, vol. 340, Jul. 25, 1992. * |
| Which regimen for H pylori eradication SCRIP No. 1861 Oct. 5, 1983, p. 23. * |
Cited By (71)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6136344A (en) * | 1995-02-06 | 2000-10-24 | Astra Aktiebolag | Oral pharmaceutical dosage form |
| US6132768A (en) * | 1995-07-05 | 2000-10-17 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors |
| US6780882B2 (en) | 1996-01-04 | 2004-08-24 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US20050004171A1 (en) * | 1996-01-04 | 2005-01-06 | Phillips Jeffrey O. | Novel substituted benzimidazole dosage forms and method of using same |
| US20040048896A1 (en) * | 1996-01-04 | 2004-03-11 | Phillips Jeffrey Owen | Novel substituted benzimidazole dosage forms and method of using same |
| US20040171646A1 (en) * | 1996-01-04 | 2004-09-02 | The Curators Of The University Of Missouri | Novel substituted benzimidazole dosage forms and method of using same |
| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US6645988B2 (en) | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| USRE45198E1 (en) | 1996-01-04 | 2014-10-14 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US6699885B2 (en) | 1996-01-04 | 2004-03-02 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and methods of using same |
| US20050042304A1 (en) * | 1996-01-04 | 2005-02-24 | Phillips Jeffrey Owen | Novel substituted benzimidazole dosage forms and method of using same |
| US20030215527A1 (en) * | 1996-01-04 | 2003-11-20 | Phillips Jeffrey Owen | Novel substituted benzimidazole dosage forms and method of using same |
| US6576258B1 (en) | 1997-07-14 | 2003-06-10 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. | Pharmaceutical formulation with controlled release of active substances |
| US6780435B2 (en) | 1997-11-14 | 2004-08-24 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6077541A (en) * | 1997-11-14 | 2000-06-20 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6096340A (en) * | 1997-11-14 | 2000-08-01 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US20030113376A1 (en) * | 1997-11-14 | 2003-06-19 | Chih-Ming Chen | Omeprazole formulation |
| US6855336B2 (en) | 1998-08-28 | 2005-02-15 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US20040131684A1 (en) * | 1998-08-28 | 2004-07-08 | Chih-Ming Chen | Omeprazole formulation |
| US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6117868A (en) * | 1998-09-16 | 2000-09-12 | Ed. Geistlich Sohne Ag Fur Chemische Industrie | Treatment of gastrointestinal ulcers or gastritis caused by microbial infection |
| US6852739B1 (en) | 1999-02-26 | 2005-02-08 | Nitromed Inc. | Methods using proton pump inhibitors and nitric oxide donors |
| US20040266828A1 (en) * | 1999-02-26 | 2004-12-30 | Nitromed, Inc. | Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use |
| EP1154771A4 (en) * | 1999-02-26 | 2005-04-20 | Nitromed Inc | Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use |
| AU781133B2 (en) * | 1999-02-26 | 2005-05-05 | Nicox S.A. | Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use |
| US7332505B2 (en) | 1999-02-26 | 2008-02-19 | Nitromed, Inc. | Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use |
| WO2000050037A1 (en) * | 1999-02-26 | 2000-08-31 | Nitromed, Inc. | Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use |
| US6245913B1 (en) | 1999-06-30 | 2001-06-12 | Wockhardt Europe Limited | Synthetic procedure for 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-IH-benzimidazole hydrochloride and its conversion to omeprazole |
| US20040157887A1 (en) * | 1999-08-26 | 2004-08-12 | Whittle Robert R. | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
| US6262085B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6667323B1 (en) | 1999-08-26 | 2003-12-23 | Robert R. Whittle | Dry-blend pharmaceutical formulations |
| US6706737B2 (en) | 1999-08-26 | 2004-03-16 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6316020B1 (en) | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
| US6667321B2 (en) | 1999-08-26 | 2003-12-23 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6667324B1 (en) | 1999-08-26 | 2003-12-23 | Robert R. Whittle | Dry blend pharmaceutical formulations |
| US6780880B1 (en) | 1999-08-26 | 2004-08-24 | Robert R. Whittle | FT-Raman spectroscopic measurement |
| US6653329B1 (en) | 1999-08-26 | 2003-11-25 | Robert R. Whittle | Granulated pharmaceutical formulations and methods for making the same |
| US6312723B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6326384B1 (en) | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
| US6262086B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
| US6444689B1 (en) | 1999-08-26 | 2002-09-03 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6733778B1 (en) | 1999-08-27 | 2004-05-11 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US7914817B2 (en) | 2000-01-05 | 2011-03-29 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Treatment of inflammatory bowel disease |
| US20030119824A1 (en) * | 2000-01-05 | 2003-06-26 | Redmond H. Paul | Treatment of inflammatory bowel disease |
| US20030099715A1 (en) * | 2000-03-28 | 2003-05-29 | Schwarz Franz Xaver | Granulated particles with masked taste |
| US20050220871A1 (en) * | 2000-03-28 | 2005-10-06 | Schwarz Franz X | Taste masking granules |
| US20080095855A1 (en) * | 2000-03-28 | 2008-04-24 | Schwarz Franz X | Taste Masking Granules |
| US20040006111A1 (en) * | 2002-01-25 | 2004-01-08 | Kenneth Widder | Transmucosal delivery of proton pump inhibitors |
| US7211590B2 (en) | 2002-08-01 | 2007-05-01 | Nitromed, Inc. | Nitrosated proton pump inhibitors, compositions and methods of use |
| US20040024014A1 (en) * | 2002-08-01 | 2004-02-05 | Nitromed, Inc. | Nitrosated proton pump inhibitors, compositions and methods of use |
| US20070179150A1 (en) * | 2002-08-01 | 2007-08-02 | Nitromed, Inc. | Nitrosated proton pump inhibitors, compositions and methods of use |
| US20040248942A1 (en) * | 2003-02-20 | 2004-12-09 | Bonnie Hepburn | Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid |
| US20040185092A1 (en) * | 2003-03-18 | 2004-09-23 | Yih Ming Hsiao | Pharmaceutical preparations of omeprazole and/or clarithromycin for oral use |
| US20060204585A1 (en) * | 2003-07-18 | 2006-09-14 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US20100297220A1 (en) * | 2003-07-18 | 2010-11-25 | Santarus, Inc | Pharmaceutical Formulation And Method For Treating Acid-Caused Gastrointestinal Disorders |
| US20050037070A1 (en) * | 2003-07-18 | 2005-02-17 | Santarus, Inc. | Pharmaceutical formulatins useful for inhibiting acid secretion and methods for making and using them |
| US8993599B2 (en) | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US20050031700A1 (en) * | 2003-07-18 | 2005-02-10 | Sanatarus, Inc. | Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders |
| US20060147522A1 (en) * | 2004-05-25 | 2006-07-06 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8815916B2 (en) | 2004-05-25 | 2014-08-26 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8906940B2 (en) | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US20050266071A1 (en) * | 2004-05-25 | 2005-12-01 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| WO2008067037A2 (en) | 2006-10-05 | 2008-06-05 | Santarus, Inc. | Novel formulations of proton pump inhibitors and methods of using these formulations |
| EP2486910A2 (en) | 2006-10-27 | 2012-08-15 | The Curators Of The University Of Missouri | Multi-chambered apparatus comprising a dispenser head |
| US20090092658A1 (en) * | 2007-10-05 | 2009-04-09 | Santarus, Inc. | Novel formulations of proton pump inhibitors and methods of using these formulations |
| US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
| US10835488B2 (en) | 2016-06-16 | 2020-11-17 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
| WO2024075017A1 (en) | 2022-10-04 | 2024-04-11 | Zabirnyk Arsenii | Inhibition of aortic valve calcification |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5599794A (en) | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic | |
| US11931463B2 (en) | All-in-one fixed-dose combination for treating Helicobacter pylori infection | |
| JP4981208B2 (en) | Taurolidine and / or taurultam for infectious ulcers or gastritis | |
| IL99471A (en) | Pharmaceutical compositions for treating helicobacter bacteria infections containing 5-fluoromethoxy-2-(3,4-dimethoxy-2-pyridyl)methylsulphinyl)-1h-benzimidazole and salts thereof in combination with an antimicrobial agent | |
| KR20010024050A (en) | Antimicrobials | |
| HK1008296B (en) | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic | |
| RU2214819C1 (en) | Container of medicinal agents for treatment and prophylaxis of gastroenteric diseases caused or mediated by infection with helicobacter pylori | |
| JPH09512262A (en) | H. Use of spiramycin for the treatment of gastrointestinal disorders caused by pylori | |
| JP2000080031A (en) | Antimicrobial agent | |
| WO2001003701A1 (en) | An oral composition having as a first active ingredient budesonide and as a second active ingredient an antibiotic, for use in intestinal conditions, especially crohn's disease | |
| WO2001003703A1 (en) | An oral composition having as a first active ingredient rofleponide and as a second active ingredient an antibiotic, for use in intestinal conditions, especially crohn's disease |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: AKTIEBOLAGET ASTRA, SWEDEN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:EEK, ARNE T.;SJOSTRAND, SVEN E.;REEL/FRAME:006551/0382;SIGNING DATES FROM 19930416 TO 19930419 |
|
| AS | Assignment |
Owner name: ASTRA AKTIEBOLAG, SWEDEN Free format text: CHANGE OF NAME;ASSIGNOR:AKTIEBOLAGET ASTRA;REEL/FRAME:008354/0516 Effective date: 19950818 |
|
| CC | Certificate of correction | ||
| AS | Assignment |
Owner name: ASTRAZENECA AB, SWEDEN Free format text: CHANGE OF NAME;ASSIGNOR:AKTIEBOLAG, ASTRA;REEL/FRAME:010841/0975 Effective date: 20000103 |
|
| FPAY | Fee payment |
Year of fee payment: 4 |
|
| REMI | Maintenance fee reminder mailed | ||
| LAPS | Lapse for failure to pay maintenance fees | ||
| STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
| FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20050204 |